Lyophilization or freeze-drying is a sublimation process that removes free water or other solvent in the form of ice. Freeze-drying is especially useful in the pharmaceutical, chemical and food industries to remove water or solvent from sensitive synthetic and biological products because it preserves their integrity and activity. The increasing use of lyophilization is driven by the escalating global demand for aseptic packaging, preservation of drugs, and the rise in the production of biologics, including protein-based therapeutics and vaccines.
During lyophilization, most of the solvent (e.g. water and/or an alcohol) is removed from a product after it is frozen and placed under vacuum. The process actually consists of three separate, but interdependent steps: freezing; primary drying (ice sublimation); and secondary drying (moisture desorption). During primary drying, 90% or more of the solvent changes directly from solid to vapor phase through sublimation without passing through a liquid phase. The remaining solvent is adsorbed on the product as moisture. Some of this solvent is subsequently desorbed during the secondary drying process to reach the desired product stability. As a result of the lyophilization process, the solvent content in the product is reduced to a low level that can no longer support biological growth or chemical reactions, while still preserving the activity and integrity of the freeze-dried product.
Freeze-drying has traditionally been carried out commercially using mechanical freezing or refrigeration systems. Although mechanical refrigeration systems may be used, it is disadvantageous to do so because very low temperatures are needed in order to cause the water vapor to freeze out in the condenser of the freeze-dryer. Operating temperatures below −50° C. adversely impact the performance, efficiency and reliability of the mechanical refrigeration systems.
Recent advancements in the field of freeze-drying employ the use of cryogenic fluids and cryogenic heat exchangers rather than mechanical refrigeration systems to carry out the freeze-drying process. The low operating temperatures required in a lyophilization process have no adverse impact on cryogenic refrigeration systems driven by liquid nitrogen with a normal boiling point of about −196° C. Cryogenic refrigeration systems for lyophilization applications are capable of providing the rapid and constant cool-down rates throughout the entire temperature range of interest. Prior art cryogenic cooling systems recover the stored cold from liquid nitrogen in specially engineered cryogenic heat exchangers where the liquid nitrogen and/or gas nitrogen will cool a heat transfer fluid which in turn cools the lyophilization chamber. Separately, the cryogenic will cool the condenser by direct expansion in the condenser coils or plates. Unfortunately, the direct use in the condenser of any refrigerant—regardless whether it is a typical hydrocarbon refrigerant or a cryogenic fluid—results in two-phase flow and uneven heat exchange inside and non-uniform ice formation on the outside of the condenser coils or plates. Also, the use of separate cooling techniques or systems for the lyophilization chamber and the condenser introduces additional complexity of the overall system, increases the system footprint and likely adds some additional costs to own and operate the system.
What is needed therefore is an advanced cryogenic refrigeration system that protects the formulations during lyophilization and that provides increased flexibility, more uniform cooling and is cost competitive with comparable mechanical refrigeration systems and overcome the disadvantages of prior cryogenic refrigeration systems.